Modafinil in Bipolar Depression: Treatment Advance or Back to the Future?

The search for effective treatments for bipolar depression is fully underway. Driven by epidemiologic prevalence, clinical need and financial profit, academic researchers and Pharma are both developing anda testing new compounds at a furious pace. Modafinil (Provigil) is a recent entrant into this mad race. Approved by the FDA for use in Excessive Daytime Sleepiness (EDS) associated with Narcolepsy, Sleep Apnea and Shift Work Sleep disorder, studies over the past five years have assessed the potential of this new drug in treating conditions that range from ADHD, Cocaine Dependence and Mood Disorders.

Modafinil is usually described as a novel compound that affects a variety of neurotransmitter systems in the brain. The purported novelty of this compound is intended to distinguish it from traditional stimulants, such as amphetamine, with which it shares numerous properties. Articles from the past two years though have more carefully examined the mechanism of action of modafinil and found that it appears to facilitate the release of dopamine and act through dopaminergic receptors in a similar fashion to traditional stimulants. A 2007 study from the European Journal of Pharmacology described it as a psychostimulant that is pharmacologically similar to, but much less potent and efficacious than, amphetamine (Dopheide, MM., et al).

Given this profile, it is no wonder that the antidepressant potential of this compound would attract interest. There is a long history of stimulant trials in the treatment of depression.

There are several, mainly indirect, lines of evidence that suggest that modafinil might be of value in the treatment of bipolar depression. First, as an agent with demonstrated wakefulness-promoting activity (it keeps people awake), it makes sense to think that it might benefit the anergia and hypersomnia that so often characterize the depressed phase of this illness. To date, the evidence on this point is mixed and limited. When used in unipolar depression in patients who had only partially responded to SSRI’s and had residual symptoms of depression, fatigue and tiredness one placebo-controlled, double-blind study showed a statistically significant advantage (Fava M, et al., 2005), another study of similar design failed to show any difference between modafinil and placebo (Dunlop, BW, et al., 2007). A third open-label trial by Ninan and colleagues in 2004 showed significant benefit. Notably, these studies focused on modafinil’s effect on residual fatigue and tiredness. To what extent modafinil would be active against other, core features of depression (feelings of guilt, disturbed sleep and eating, hopelessness) is unknown.

A second, indirect line of evidence bearing on this drug’s potential in bipolar depression is a single study of modafinil monotherapy for atypical depression (a syndrome that shares many symptoms with bipolar depression.) Structured somewhat unusually, patients were first treated in an open-label fashion and then randomized to either placebo or active drug for continuation treatment. Relative advantage for the drug was found in the open-label but not the continuation phase of this study. Not definitive but intriguing.

Last is the single and only direct study of modafinil in bipolar depression. Done by Mark Frye and colleagues at UCLA and published in the American Journal of Psychiatry in 2007, this research tested modafinil augmentation in 85 patients with bipolar depression who were inadequately responsive to a mood stabilizer with or without an antidepressant. Performed over 6 weeks, this placebo-controlled, double-blind study showed a rapid, significant and sustained advantage of modafinil on depressive symptoms. So what conclusions can be drawn on the overall efficacy of modafinil for bipolar depression at this time?

First, with the exception of the one well-controlled study by Frye on patients with bipolar depression, most of the evidence to date comes from open-label, non-blinded studies, often addressing other forms of depression. Second, all of the research has evaluated short-term efficacy; whether longer-term and prophylactic benefit will be demonstrated is anybody’s guess. Third, while modafinil was not associated with any serious side-effects, including hypomanic/manic switching, its long-term safety profile requires documentation. Last, under closer inspection, modafinil appears to have considerable similarity to traditional stimulants. An article by P.J. Carlson in 2004 in the journal Bipolar Disorders showed that methylphenidate (Ritalin) and amphetamine (Adderall or Desoxsyn) effectively treated residual symptoms of depression and fatigue in patients with bipolar depression. How this new drug compares to stimulants and other antidepressant and mood stabilizing drugs used in bipolar depression is unknown. The answers to these questions will help determine whether modafinil represents a truly novel agent with a distinctive mechanism of action or is simply old wine in a new bottle. In the meantime, I’ll use it sparingly and give some reconsideration to old-fashioned stimulants.